HIV-1 CD8+ T cell emergence, evolution and virus control
File(s)
Author(s)
Dalel, Jama
Type
Thesis
Abstract
HIV-1-specific CD8 T cells play a critical role in controlling HIV-1 viremia and slowing disease progression in the early stage of the infection. CD8 T cell potency and survival during HIV-1 depends on cytokines like Interleukin-21 (IL-21). However, we still lack a vaccine immunogen design that leverages a clear rationale to induce effective CD8 T-cell responses against HIV-1. The contribution of CD8 T cell recognition of specific HIV-1 epitopes to viral inhibition is not clear. Furthermore, little is known about the signaling dynamics of IL-21 and its receptor (IL-21R) during this response.
My data shows IL-7 and IL-21 cytokines drive efficient expansion of HIV-1-specific-CD8 T cells while limiting drive towards terminal differentiation. Furthermore, IL-21Rhigh CD8 T cells displayed greater dysfunction associated with lack of HIV-1 control, while IL-21 directly downregulated IL-21R through shedding of receptor.
I show how the immune response of HIV-1 controllers focus early, and targets significantly more GAG peptides and fewer ENV. Exclusive targeting of specific regions in GAG was associated with the lowest viral loads and highest CD4 T-cell counts, while targeting of GAG protein was linked with the greatest cross-clade viral inhibition irrespective of HLA-restriction.
Overall, my research shows IL-21R could be a biomarker to inform on CD8 T cell dysfunction during HIV-1 infection. While my antigen-specific expansion protocol allowed me to interrogate the contribution of CD8 T-cell specificity to viral inhibition. Most of all, my results show that the specificity and early focusing of the CD8 T-cell response is critical to in vivo control of HIV-1 infection. Taken together, my data provides significant support for continued efforts to develop HIV-1 vaccines based on CD8 T cell signature in controllers while exploiting cytokines/receptors such as IL-21/R for better HIV-1 immunotherapeutic approaches and monitoring.
My data shows IL-7 and IL-21 cytokines drive efficient expansion of HIV-1-specific-CD8 T cells while limiting drive towards terminal differentiation. Furthermore, IL-21Rhigh CD8 T cells displayed greater dysfunction associated with lack of HIV-1 control, while IL-21 directly downregulated IL-21R through shedding of receptor.
I show how the immune response of HIV-1 controllers focus early, and targets significantly more GAG peptides and fewer ENV. Exclusive targeting of specific regions in GAG was associated with the lowest viral loads and highest CD4 T-cell counts, while targeting of GAG protein was linked with the greatest cross-clade viral inhibition irrespective of HLA-restriction.
Overall, my research shows IL-21R could be a biomarker to inform on CD8 T cell dysfunction during HIV-1 infection. While my antigen-specific expansion protocol allowed me to interrogate the contribution of CD8 T-cell specificity to viral inhibition. Most of all, my results show that the specificity and early focusing of the CD8 T-cell response is critical to in vivo control of HIV-1 infection. Taken together, my data provides significant support for continued efforts to develop HIV-1 vaccines based on CD8 T cell signature in controllers while exploiting cytokines/receptors such as IL-21/R for better HIV-1 immunotherapeutic approaches and monitoring.
Version
Open Access
Date Issued
2022-06-27
Date Awarded
01/01/2023
License URL
Advisor
Gilmour, Jill
Imami, Nesrina
Makinde, Julia
Sponsor
Imperial College London
Publisher Department
Department of Infectious Disease
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)